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Abstract

Background

To date, there is no consensus on the utility of screening procedures for the early
detection of endometrial cancer. The value of transvaginal ultrasound for screening
of asymptomatic endometrial cancer has been discussed controversially. This study
was conducted to evaluate whether asymptomatic patients with endometrial cancer have
a better prognosis than symptomatic patients with endometrial cancer diagnosed after
postmenopausal bleeding.

Methods

In the present multi-center study, the effect of the presence of postmenopausal bleeding
on prognosis was evaluated retrospectively in 605 patients with endometrial cancer
using patients' files. 543 patients (133 patients were asymptomatic, 410 patients
were symptomatic) with endometrioid endometrial cancer were enrolled in all further
analysis. Student's t-test, Cox regression analysis and Kaplan-Meier analysis were
used were appropriate.

Results

Presence/absence of a postmenopausal bleeding was not associated with tumor stage
(p = 0.2) and age at diagnosis (p = 0.5). Asymptomatic patients with endometrial cancer
had a significantly higher rate of well and moderate-differentiated tumors compared
to symptomatic patients (p = 0.008). In univariable and multivariable survival analysis,
tumor stage, tumor grade, and patients' age at diagnosis, but not presence/absence
of a postmenopausal bleeding, were associated with disease free and overall survival.

Conclusion

Asymptomatic patients with endometrial cancer have a higher rate of well differentiated
tumors compared to patients with a postmenopausal bleeding prior to diagnosis. The
prognosis of both groups of patients was similar.

Background

Endometrial cancer is the most common gynecological malignancy in developed countries
with an estimated 39,000 newly diagnosed cases in the United States in 2007. Although
many patients are diagnosed with an early stage disease, 7400 deaths will occur [1].

Approximately 90% of women with endometrial cancer have abnormal uterine bleeding
as the only presenting complaint leading to the diagnosis of the disease [2]. To date, there is no consensus on the utility of screening procedures for the early
detection of endometrial cancer [3-8]. It has been suggested that screening of asymptomatic endometrial cancer by transvaginal
ultrasound before the onset of clinical symptoms, i.e., postmenopausal bleeding, leads
to an earlier diagnosis [8]. As in other malignancies, it can be hypothesized that an earlier diagnosis leads
to a lower stage of disease, a less radical surgery, a therapy with less side effects
and, subsequently, a better prognosis of affected patients.

Interestingly, relatively few studies are available investigating whether asymptomatic
patients with endometrial cancer have a better prognosis than those detected after
the onset of a postmenopausal bleeding. Gerber et al. performed a retrospective study in 190 postmenopausal patients with symptomatic
endometrial cancer and 16 asymptomatic patients showing no difference in survival
in this relatively small series [7]. Osmer et al. compared 61 and 22 postmenopausal women with symptomatic and asymptomatic endometrial
cancer, respectively. Patients with asymptomatic endometrial cancers showed a less
myometrial tumor infiltration and more well differentiated tumors than symptomatic
patients. A better prognosis for asymptomatic patients has been suggested [8]. Kimura et al. reviewed a total of 304 endometrial cancer patients [9]. Patients diagnosed with asymptomatic endometrial cancer showed a significantly better
5-year overall survival rate than the patients diagnosed after the onset of postmenopausal
bleeding. The distribution of clinical stages and histological grades did not differ
between both groups.

The aim of the present study was to estimate whether asymptomatic patients with endometrial
cancer have a better prognosis than symptomatic patients with endometrial cancer diagnosed
after postmenopausal bleeding in a large series of postmenopausal patients with endometrial
cancer in a multi-center study.

Methods

Patients

Clinical data were obtained retrospectively from files at the Medical University of
Vienna, Department of Obstetrics and Gynecology, the Landeskrankenhaus Klagenfurt,
Department of Obstetrics and Gynecology, and the Innsbruck Medical University, Department
of Obstetrics and Gynecology. Six hundred five consecutive patients (Medical University
of Vienna: n = 388, Landeskrankenhaus Klagenfurt: n = 79, Innsbruck Medical University:
n = 138) with histological confirmed endometrial cancer undergoing surgery between
December 1995 and January 2005 were included in our study. Five hundred forty three
patients with endometrioid endometrial cancer were enrolled in all further analysis.
Other histological subtypes were excluded from further analysis.

Based on patients' history and on the clinical examination performed by the referring
physician and at time of referral to hospital, patients were classified into two groups
according to presence (symptomatic patients) or absence (asymptomatic patients) of
postmenopausal bleeding. Asymptomatic patients were defined as neglecting a type of
bleeding in the previous 12 months, as having no signs of bleeding seen during the
gynecological examination performed by the referring physician and at time of referral
to hospital, and as not having any other symptoms indicative for endometrial cancer.
Patients' personal history has been performed in the participating study centers in
a standardized way. One of the most important questions was presence/absence of postmenopausal
bleeding. This has been clearly documented in all patients' files.

Clinical management

A guideline by the Austrian Society of Gynecology and Obstetrics (OEGGG) and the Austrian
Society of Gynecologic Oncology (AGO) recommends endometrial sampling in cases of
a postmenopausal bleeding or an endometrial thickness > 11 mm in asymptomatic women
[10]. Asymptomatic women included in our study are real asymptomatic cases detected by
"quasi-screening" and did not seek care for other reasons. Diagnosis of endometrial
cancer was established by hysteroscopy, dilatation and curettage. Subsequently, patients
were treated by hysterectomy, bilateral salping-oophorectomy, pelvic and in selected
cases paraaortic lymphadenectomy. In cases of lymph node metastases, postoperative
radiotherapy was applied according to standardized treatment protocols. Histological
staging and grading was performed according to the current International Federation
of Gynecology and Obstetrics (FIGO) classification on basis of the final pathologic
evaluation of hysterectomy specimen.

Patients were followed up in regular intervals after surgery, including inspection,
vagino-rectal and screening for serum tumor marker evaluation. In cases of clinically
suspicious findings and/or tumor marker elevation computed tomography was performed.
The same protocols for treatment and follow-up were used in all participating centers.

Statistical analysis

Values are given as means (standard deviation [SD]) for evenly distributed values.
Metric parameters were compared using Student's t-test. All data a Student's t-test
was used for, were normally distributed. Nominal parameters were compared using Chi
square test. Survival probabilities were calculated by a univariable Cox regression
analysis (metric variables) or a product limit method of Kaplan and Meier using the
log-rank test (categorical variables). A multivariable Cox regression model was performed
comprising tumor stage (FIGO I vs. FIGO II vs. FIGO III vs. FIGO IV), tumor grade
(G1 vs. G2 vs. G3), age at diagnosis, and presence/absence of irregular bleeding.
The results were analyzed for the endpoint of disease-free and overall survival. Survival
times of patients disease-free or still alive were censored with the last follow-up
date. The proportional hazards assumption has been checked and found not to be violated.
P-values of < 0.05 were considered statistically significant. We used the statistical
software SPSS 11.0 for Windows (SPSS 11.0, SPSS Inc., Chicago, IL) for statistical
analysis.

Institutional review board

The present study was approved by our institutional review board, the Ethics-Committee
of the Medical University of Vienna and the Vienna General Hospital - AKH.

Results

Patients' characteristics of asymptomatic/symptomatic patients with endometrial cancer
are shown in Table 1. Asymptomatic patients with endometrial cancer had a significantly higher rate of
well differentiated tumors. FIGO tumor stages and patients' age were evenly distributed.
In univariable and multivariable survival analysis, tumor stage, tumor grade, and
patients' age at diagnosis were associated with disease free and overall survival
(Table 2, Table 3). In a multivariable survival analysis presence/absence of a postmenopausal bleeding
prior to diagnosis was not associated with disease free or overall survival (Table
3). Kaplan-Meier curves for the influence of presence/absence of a postmenopausal bleeding
on disease-free (Figure 1) and overall (Figure 2) survival are shown.

Discussion

We present data on the prognostic value of presence/absence of a postmenopausal bleeding
prior to diagnosis in large series of patients with endometrial cancer in a multi-center
study. In parallel to previous studies [9], we did not ascertain a significant difference in prognosis between asymptomatic
and symptomatic patients.

Screening for gynecological malignancies has been advocated in order to diagnose diseases
at earlier stage leading to earlier treatment with less side-effects and better prognosis
[11]. To date, screening tools for endometrial cancer have not been identified. Transvaginal
ultrasound has been suggested to detect endometrial cancer in an earlier stage before
the onset of clinically recognizable symptoms [6]. Our study falls short of showing any statistically significant difference in disease-free
and overall survival of affected patients.

Based on our study design we cannot extrapolate our results to a real screening situation.
Although having no formally organized screening program in Austria, the majority of
postmenopausal women routinely see their gynecologist once a year, i.e. opportunistic
screening. Besides the PAP smear, a transvaginal sonography is routinely performed
during this examination. Based on the currently available evidence [5], a guideline by the Austrian Society of Gynecology and Obstetrics (OEGGG) and the
Austrian Society of Gynecologic Oncology (AGO) recommends endometrial sampling in
cases of asymptomatic women and an endometrial thickness > 11 mm [10]. This might be the most likely reason for having only 3/4 of women with endometrial
cancer presenting with postmenopausal bleeding.

Of note, our study was not set out to evaluate the advantages or disadvantages of
a transvaginal ultrasound in the screening of endometrial cancer. Studies demonstrating
a positive effect of performing routine endometrial cancer screening on overall mortality
would possibly have to include hundreds of thousands of women based on the relatively
low incidence of the disease, the high rate of symptomatic women in early stage disease,
and the good prognosis of affected women. Due to high costs and missing data on the
reliability of TVS as screening tool for endometrial cancer the realization of a study
like this would be hard to justify [12,13]. We speculate that such large-scale studies will not be performed and completed in
the near future.

Our study supports previously published studies indicating that tumor biology in asymptomatic
patients was different than in symptomatic patients [8]. This possibly reflects a higher propensity of low-differentiated tumors to cause
postmenopausal bleeding than well/moderate differentiated endometrial cancers.

Our study has strengths and weaknesses, namely the retrospective study design, the
extraction of information from patients' files, the relatively low number of events
due to a generally good prognosis of affected patients, and the relatively short time
of follow up. Another interesting point to mention is the relatively high percentage
of women having advanced FIGO stages, i.e., FIGO II-IV, and still not having any symptoms.
This can be easily explained in patients with FIGO IIIA, but not for other stages.
Of note, we double-checked all FIGO stages and found our numbers to be correct. This
has to be considered when interpreting the results of our study.

Conclusion

To conclude, asymptomatic patients with endometrial cancer undergoing surgery have
a higher rate of well and moderate differentiated tumors compared to patients with
a postmenopausal bleeding prior to diagnosis. The prognosis of both groups of patients
was similar.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

V.S. initiated the design of the study with L.H. and A.R. and was involved in developing
and conducting the study, wrote drafts of the paper and reviewed the manuscript. M.S.,
K.H-F., H.L. and N.C. obtained the data from medical records, prepared the data for
analysis and participated in reviewing of the manuscript. S.P. carried out statistical
analysis and participated in reviewing the manuscript. A.R. and L.H. initiated the
study design with V.S., coordinated analysis, interpreted results and participated
in the writing and reviewing of the paper. All authors have read and approved the
final manuscript.